Evoked Response to Stimulation

ABSTRACT

In an embodiment, an evoked response of an electrode may be determined. The evoked response may be compared to other evoked responses to determine the location of the electrode. The evoked response may be measured during electrode implantation so that desired changes can be made and if electrodes are being implanted in both the right and left hemisphere, it can be determined that both electrodes are positioned in the same target in both the right and left hemisphere. The evoked responses may be used to determine if the stimulation target has functional connectivity with the treatment areas. Stimulation parameters for the electrodes may be determined in a closed-loop configuration and used to stimulation the electrodes in an open-loop configuration designed to reduce the probability of neurological events such as seizures.

This is a continuation-in-part of U.S. application Ser. No. 11/380,752,filed Apr. 28, 2006 (Attorney Docket No. 011738.00310), which in turnclaims priority to U.S. Provisional Application Ser. No. 60/780,954filed Mar. 10, 2006 (Attorney Docket No. 011738.00294), both of whichare incorporated herein by reference in their entirety.

BACKGROUND OF THE INVENTION

The invention relates to the evaluation, warning and treatment ofneurological disorders such as epilepsy, devices for such evaluation,warning and treatment, including external and implantable devices andsystems, and methods and techniques by which the devices and systemsoperate, and the methods by which patients suffering disorders such asepilepsy are evaluated, warned, and treated by electrical stimulation orsome other modality. Specifically, the invention discloses aprobabilistic approach for issuing warnings and/or triggering therapydelivery without relying on conventional event detection or predictionapproaches. This may result in therapy delivery before the onset of aneurological event, such as seizure, or even before the onset of apre-event state, thus preventing the neurological event from occurring.

BRIEF DESCRIPTION OF THE PRIOR ART

The objective of currently approved seizure therapies, whetherpharmacological or electrical, is to treat seizures through an“open-loop” approach. In the case of drugs, these are dosed based ontheir half-life and therapeutic ratio, so as to maintain relativelyconstant drug serum concentrations round-the-clock and avoid largefluctuations (drops or rises in concentrations), that may leave thesubject relatively unprotected (if low) or may cause dose-related sideeffects (if high). In the case of electrical stimulation such as withthe Neurocybernetic prosthesis (Cyberonics, Houston, Tex.), currents aredelivered periodically, round-the-clock.

For drugs and electrical stimulation, the dosing/stimulation schedule(not the dose or electrical current intensity) of approved therapiesdoes not take into account the actual frequency of seizures or theirtemporal (e.g., circadian) distributions: The approach is fundamentallythe same for a subject with multiple daily seizures or for one with onlyone every few years, or if the seizures occur only at night or at anytime during the daylight. Adjustments in treatment, if any, are made atcertain time intervals based on the number of seizures reported by thesubject (by seizure diary) or on the frequency and type of side effectsover that interval.

Since the advent of automated means for detecting seizures (see, e.g.,U.S. Pat. No. 5,995,868 Osorio et al.; Neuropace; Litt) and of methodsthat allegedly predict the onset of seizures (see, e.g., patents issuedto lasemidis; Litt; Hively, Lenhertz), warning and closed-looptherapeutic intervention in response to the output of those methods isnow possible. This approach is potentially highly temporo-spatiallyselective, minimizing adverse effects and unnecessary treatments and intheory, may be superior to open-loop. However, all known, usefulprior-art closed-loop therapies restrict intervention to be contingentupon discrete event detections and require that signals (EEG or othertypes) be continuously monitored (around the clock and for the life ofthe subject) to enable these event detections.

In the case of seizure detection-based closed-loop control, knowndevices attempt to detect the occurrence of a seizure through analysisof biological signals and respond with electrical stimulation or othertherapy. In the case of seizure prediction-based closed-loop control,known devices attempts to detect the occurrence of a pre-seizure state,again through some analysis of biological signals, and respond withdelivery of some contingent therapy.

These approaches to closed-loop control remain based on relatively shorttime scales of changes (seconds to minutes in the case of seizuredetection, seconds to a few hours in the case of seizure prediction) andtypically are based on the assumption that the detection is connected ina dynamically contiguous way with the ongoing or impending seizure. Inaddition, these approaches ignore temporal correlations between seizuresincluding long-range dependencies.

SUMMARY OF THE INVENTION

The following represents a simplified summary of some embodiments of theinvention in order to provide a basic understanding of various aspectsof the invention. This summary is not an extensive overview of theinvention. It is not intended to identify key or critical elements ofthe invention or to delineate the scope of the invention. Its solepurpose is to present some embodiments of the invention in simplifiedform as a prelude to the more detailed description that is presentedbelow.

In an embodiment, a first electrode may be implanted in a patient'sbrain in a first hemisphere. By applying stimulation pulses to the firstelectrode, a first evoked response may be measured. The first evokedresponse may be compared to previous or subsequent evoked responses todetermine the part of the brain that is being stimulated by the firstelectrode. A second electrode may be implanted in a second hemisphere ofthe patient's brain and evoked responses from the second electrode maybe measured. The evoked response from the second electrode may becompared with the response evoked by stimulation of the first electrodeto verify that the first and second electrodes are stimulating the samepart of the brain, just in different hemispheres. In an embodiment thismay be done inter-operatively (e.g., during the electrode implantingprocess).

In an embodiment, a closed-loop detection algorithm may be used todetermine stimulation parameters that reduce the probability of aneurological disorder such as a seizure. An implantable medical devicemay be implanted and used to provide electrical stimulation inaccordance with the parameters to the first and second electrodes in anopen-loop manner. In an embodiment, the stimulation may be in amonopolar configuration with the first and second electrodes being usedas cathodes while a case of the implantable medical device is used ananode.

BRIEF DESCRIPTION OF THE DRAWINGS

The present invention is illustrated by way of example and not limitedin the accompanying figures in which like reference numerals indicatesimilar elements and in which:

FIG. 1 is a schematic view of a medical device implanted in a patientthat monitors cardiac and nervous system disorders in accordance with anaspect of the invention.

FIG. 2 is a simplified block diagram of the medical device shown in FIG.1 in accordance with an aspect of the invention.

FIG. 3 is a graphical representation of various signals sensed by themedical device as shown in FIG. 1 in accordance with an aspect of theinvention.

FIG. 4 shows an apparatus that supports reporting neurological data inaccordance with an aspect of the invention.

FIG. 5 is a schematic diagram of a system utilizing the above-describedembodiments and allowing remote monitoring and diagnostic evaluation ofat risk patients in accordance with an aspect of the invention.

FIG. 6 is a schematic diagram of an alternative system utilizing theabove-described embodiments and allowing remote monitoring anddiagnostic evaluation of at risk patients in accordance with an aspectof the invention.

FIG. 7 is a chart of seizure frequency as a function of time of day insome subjects.

FIG. 8 is a chart of simulated probability of seizure as a function oftime of day, for a supposed patient.

FIG. 9 is a chart of probability of seizures as a function of timeduring a stimulation cycle in some subjects.

FIG. 10 is a chart of probability of seizures as a function of time fromonset of stimulation in some subjects.

FIG. 11 is a chart of probability of seizures as a function of time frombeginning of seizure in some subjects.

FIG. 12 is a chart of probability of seizures as a function of timerelative to therapy delivery in some subjects.

FIG. 13 illustrates a process of determining the location of anelectrode using an evoked response in accordance with an aspect of theinvention.

FIG. 14 illustrates a process of applying stimulation to an electrode inaccordance with an aspect of the invention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

Overview

The following discloses approaches to patient evaluation, warning andtreatment, referred herein to as “probabilistic” approaches, that arenot based on a strict binary approach for discrete event detection(i.e., “0” for no detection and “1” for detection), or prediction (i.e.,“0” for no issuance of prediction and “1” for issuance of a prediction).Instead, disclosed are techniques that estimate probability distributionfunctions or cumulative distribution functions, “built” relying onrepresentative historical profiles, comprising information in shortand/or long timescales obtained at times that may be intermittent ortemporally discontinuous from each other or from other events ofinterest.

Conventional “open-loop” control (i.e., that which is implemented in theabsence of immediate information or “feedback”) is comparatively easy toimplement, as it does not require that a device monitor in real-time,the state of the subject and decipher the relevant information.Conventional closed-loop control is a more powerful class of therapythan conventional open-loop, and while more expensive/complicated thanopen-loop, it offers greater opportunity for success in certain cases.Both approaches, closed-loop and open-loop, as currently utilized, haveadvantages and disadvantages relative to one another. In the embodimentsdisclose herein are techniques, termed “probabilistic closed-loop,” thatprovide a new approach to therapy or control that draws on the strengthsof the two approaches and attempts to advance beyond what may beperceived as their respective limitations.

In the embodiment of treating or controlling seizures, probabilisticcontrol of seizures is based on the following observations: (1) theprobability of seizure occurrence is not solely a function of signalchanges in the system but of multiple factors; (2) seizure probabilitychanges as a function of state, being lowest in the period immediatelyfollowing the termination of seizures; and (3) the anti-seizure effectsof closed-loop electrical stimulation, either local (delivered directlyto epileptogenic tissue) or remote (delivered to epileptogenic tissuevia a structure connected to it), of epileptogenic tissue are bothclosely temporally correlated with delivery of currents (immediateeffect) and persist for some time beyond cessation of stimulation(“carry-over” effect) [Osorio et al 05, Annals of Neurology].

Depending on the duration and degree of protective “carry-over” effect,stimulation parameters may be adjusted to attain a state of protectionthat minimizes seizure occurrence probability and whose level or degreeof protection is a function of this probability. This strategy, referredto as probabilistic closed-loop, may be in certain cases, preferable toconventional closed-loop treatment, which operates only in response toevent detections (either seizure detections or, in the case of“prediction,” the detection of a pre-seizure state) and provides eventdetection-contingent therapy. Of course, both options may be usedtogether, i.e., one does not necessarily preclude the other. Forexample, contingent therapy such as stimulation may be used to treatbreakthrough seizures. Moreover, if future studies show, as did onestudy [Osorio 05], that short closed-loop trials help identifyefficacious parameters, they may be followed by open-loop phases, makingopen-loop intelligent or adaptive (“intelligent open-loop”).

The “probabilistic closed-loop” may evolve, under certain circumstancesand in certain cases, into “intelligent” open-loop defined as lackingimmediate or real-time information/“feedback”, but operating accordingto changes in estimates of seizure probability (as a function of timeand/or state) which were calculated using past information and which maybe updated/improved (as a function of time and/or state) but not inreal-time, using new information. “Intelligent” open-loop does notrequire that implantable monitoring devices be used for real-time signalprocessing/analysis for the detection/prediction/quantification ofseizures nor that in-hospital monitoring be performed. Instead, portablemonitoring devices for ambulatory/home monitoring may be used. Themonitoring devices may obtain signals such as EEG, ECoG, EKG or others,preferably via telemetry and periods of intensive monitoring andparameter optimization (with or without closed-loop therapy) may becarried out as often as indicated. By decreasing reliance on continuoussignal monitoring, this alternative therapeutic regimen simplifiesoperation and decreases power requirements, factors that translate intosmaller, more efficient and less costly implantable therapy devices.

As used herein, “open-loop” control is generally therapy that isadministered according to a program that depends on time, without takinginto account real-time information about the state of the subject.“Closed-loop” is generally refers to the administration of therapy thatis dependent upon information about the state of the subject and therapyis triggered if and when seizures are either detected or predicted.

As used herein, “intelligent open-loop” is generally the triggering ofinterventions dictated by changes in probability of seizure occurrenceestimated using past information. For example, if the mean or medianhalf-life duration of the protective carry-over effect of electricalstimulation in a given patient lasts 20 minutes, as determined withclosed-loop or probabilistic closed-loop modalities, electricalstimulation will be delivered again 20 min after each trial, round-theclock. This modality does not use real-time but past information.

As described herein, “probabilistic closed-loop” does not requiredetection or prediction of seizures for triggering anintervention/therapy delivery, but rather, probabilities that areassociated with: (a) an unacceptable value (for the subject or for thesituation, etc.) related to safety, social or other risks; (b) a changein value which is rapid and/or large in magnitude for that subject,brain/systems state, time of day or activity; (c) weakening of the“steady-state” of protection (loss of a “carry-over” effect) afforded byprevious therapy delivery or inability to attain the sufficient degreeof “carry-over” protection following therapy delivery.

Embodiments of the Medical Device System

In an embodiment, the invention may be implemented within an implantableneurostimulator system, however, those skilled in the art willappreciate that the techniques disclosed herein may be implementedgenerally within any implantable medical device system including, butnot limited to, implantable drug delivery systems, and implantablesystems providing stimulation and drug delivery. The implantable medicaldevice may provide therapeutic treatment to neural tissue in any numberof locations in the body including, for example, the brain (whichincludes the brain stem), the vagus nerve, the spinal cord, peripheralnerves, etc. The treatment therapies can include any number of possiblemodalities alone or in combination including, for example, electricalstimulation, magnetic stimulation, drug infusion, brain temperaturecontrol, and/or any combination thereof.

In addition, aspects of the invention may be embodied in various formsto analyze and treat nervous system and other disorders, namelydisorders of the central nervous system, peripheral nervous system, andmental health and psychiatric disorders. Such disorders include, forexample without limitation, epilepsy, Sudden Unexpected Death inEpilepsy Patients (SUDEP), Parkinson's disease, essential tremor,dystonia, multiple sclerosis (MS), anxiety (such as general anxiety,panic, phobias, post traumatic stress disorder (PTSD), and obsessivecompulsive disorder (OCD)), mood disorders (such as major depression,bipolar depression, and dysthymic disorder), sleep disorders(narcolepsy), obesity, tinnitus, stroke, traumatic brain injury,Alzheimer's, and anorexia.

In certain embodiment, the biological signals that may selected, storedand/or reported in accordance with various aspects of the invention mayinclude any number of sensed signals. Such biological signals caninclude, for example, electrical signals (such as EEG, ECoG and/or EKG),chemical signals (such as change in quantity of neurotransmitters),temperature signals, pressure signals (such as blood pressure,intracranial pressure or cardiac pressure), respiration signals, heartrate signals, pH-level signals, activity signals (e.g., detected by anaccelerometer), and/or peripheral nerve signals (cuff electrodes on aperipheral nerve). Such biological signals may be recorded using one ormore monitoring elements such as monitoring electrodes or sensors. Forexample, U.S. Pat. No. 6,227,203 provides examples of various types ofsensors that may be used to detect a symptom or a condition or a nervoussystem disorder and responsively generate a neurological signal. Inaddition, various types of physiologic activities may be sensedincluding, for example, brain, heart and/or respiration.

As discussed, the techniques disclosed herein are suitable for usewithin any implantable medical device system that receives signalsassociated with the physiological conditions being sensed, a memorycomponent, and a processing component (logic or software) that storesdata records in data structures. Certain techniques are also suitablefor implantable medical devices with even lesser functionality. Forexample, in an embodiment where the implantable unit applies open-loopelectrical stimulation in a desired pattern, the implantable device mayinclude only those elements necessary to provide the pattern ofelectrical stimulation. However, an implantable medical device withgreater functionality may also be used to provide open-loop stimulationas well as one or more of the additional features discussed herein.

Manual indication of a seizure or other event may be achieved through anexternal programmer device. The patient (or caregiver) may push a buttonon the external programmer device, while communicating with theimplanted device. This may provide a marker of the sensed data (forexample, in the event the patient is experiencing a neurological event).

In assessing the risk of SUDEP, for example, prolonged ECG recordingsmay be possible (e.g., recording all data during sleep since theincidence of SUDEP is highest in patients during sleep). Post-processingof the signal can occur in the implanted device, the patient's externaldevice, a clinician external device, and/or another computing device.Intermittently (e.g., every morning, once/week, following a seizure), apatient may download data from the implantable device to the patientexternal device (as will be discussed further herein), which may then beanalyzed by the external device (and/or sent through a network to thephysician) to assess any ECG abnormalities. If an abnormality isdetected, the device may notify the patient/caregiver. At that time, thepatient/caregiver may inform the healthcare provider of the alert toallow a full assessment of the abnormality. The clinician externaldevice may also be capable of obtaining the data from the implanteddevice and conducting an analysis of the stored signals. If apotentially life-threatening abnormality is detected, the appropriatemedical treatment may be prescribed (e.g., cardiac abnormality: apacemaker, an implantable defibrillator, or a heart resynchronizationdevice may be indicated or respiration abnormality: CPAP, patientpositioning, or stimulation of respiration may be indicated). These datamay be used to build probability estimates as a function of time, state(asleep or in seizure) and activities (exercising) to enable therapiesat times of high risk to prevent an event or, in the case of SUDEP, afatal outcome.

Moreover, the implantable medical device may also monitor EEG signalsfrom intracranially implanted leads. This may allow the implantedmedical device to collect cardiovascular and neurological signals inclose proximity to detected neurological events as well as notify thepatient/caregiver of a prolonged event (and/or status epilepticus). Theimplantable medical device may detect neurological events and analyzethe peri-ictal signals and initiate loop recording.

Again, it will be appreciated that alternative embodiments of theimplantable medical device may also be utilized. For example, cardiaclead(s), a sensor stub, and/or a wearable patch may be used tofacilitate detection of a neurological event and the recording of dataand signals pre and post event. An integrated electrode may also be usedthat senses ECG signals as described in U.S. Pat. No. 5,987,352.Optionally, the implantable medical device may warn/alert the patient 12via buzzes, tones, beeps or spoken voice (as substantially described inU.S. Pat. No. 6,067,473) via a piezo-electric transducer incorporatedinto the housing of implantable medical device. The sound may betransmitted to the patient's inner ear.

In another embodiment, the monitor may be implanted cranially in thepatient 12 (FIG. 1). In such an embodiment, the monitor may beconstructed as substantially described in U.S. Pat. Nos. 5,782,891 and6,427,086. EEG sensing may be accomplished by the use of integratedelectrodes in the housing of the monitor, cranially implanted leads, andor leadless EEG sensing.

FIG. 1 illustrates an implantable system 10 including an implantablemedical device 20 implanted in a patient 12. Optionally, the implantablemedical device 100 may monitor one or more biological signals/conditionsof the patient via lead 19 and monitoring/sensing elements 30 and 32 (inthe embodiment, the biological conditions are cardiac and neurologicalfunctions of patient 12). Stored diagnostic data may be uplinked andevaluated by an external computing device 23 (e.g., a patient's orphysician's programmer) via a 2-way telemetry, using for example,antenna 24 to relay radio frequency signals 22, 26 between implantablemedical device 100 and external computing device 23. An external patientactivator that may be located on external computing device 23 mayoptionally allow patient 12, or care provider (not shown), to manuallyactivate the recording of diagnostic data.

FIG. 2 depicts a block diagram of the electronic circuitry ofimplantable medical device 100 of FIG. 1 in accordance with anembodiment of the invention. Implantable medical device 100 comprises aprimary control circuit 220 and may be similar in design to thatdisclosed in U.S. Pat. No. 5,052,388. Primary control circuit 220includes sense amplifier circuitry 224, a crystal clock 228, arandom-access memory and read-only memory (RAM/ROM) unit 230, a centralprocessing unit (CPU) 232, digital logic circuit 238, a telemetrycircuit 234, and stimulation engine circuitry 236, all of which aregenerally known in the art.

Implantable medical device 100 may include internal telemetry circuit234 so that it is capable of being programmed by means of externalprogrammer/control unit 23 via a 2-way telemetry link. Externalprogrammer/control unit 23 communicates via telemetry with implantablemedical device 100 so that the programmer can transmit control commandsand operational parameter values to be received by the implanted device,and so that the implanted device can communicate diagnostic andoperational data to the programmer 23. For example, programmer 23 may beModels 9790 and CareLink® programmers, commercially available fromMedtronic, Inc., Minneapolis, Minn. Various telemetry systems forproviding the necessary communications channels between an externalprogramming unit and an implanted device have been developed and arewell known in the art. Suitable telemetry systems are disclosed, forexample, in U.S. Pat. Nos. 5,127,404; 4,374,382; and 4,556,063.

Typically, telemetry systems such as those described in the abovereferenced patents are employed in conjunction with an externalprogramming/processing unit. Most commonly, telemetry systems forimplantable medical devices employ a radio-frequency (RF) transmitterand receiver in the device, and a corresponding RF transmitter andreceiver in the external programming unit. Within the implantabledevice, the transmitter and receiver utilize a wire coil as an antenna24 for receiving downlink telemetry signals and for radiating RF signalsfor uplink telemetry. The system is modeled as an air-core coupledtransformer. An example of such a telemetry system is shown in U.S. Pat.No. 4,556,063.

In order to communicate digital data using RF telemetry, a digitalencoding scheme such as is described in U.S. Pat. No. 5,127,404 can beused. In particular, a pulse interval modulation scheme may be employedfor downlink telemetry, wherein the external programmer transmits aseries of short RF “bursts” or pulses in which the interval betweensuccessive pulses (e.g., the interval from the trailing edge of onepulse to the trailing edge of the next) is modulated according to thedata to be transmitted. For uplink telemetry, a pulse positionmodulation scheme may be employed to encode uplink telemetry data. Forpulse position modulation, a plurality of time slots are defined in adata frame, and the presence or absence of pulses transmitted duringeach time slot encodes the data. For example, a sixteen-position dataframe may be defined, wherein a pulse in one of the time slotsrepresents a unique four-bit portion of data.

Programming units such as the above-referenced Medtronic Models 9790 andCareLink® programmers typically interface with the implanted devicethrough the use of a programming head or programming paddle, a handheldunit adapted to be placed on the patient's body over the implant site ofthe patient's implanted device. A magnet in the programming head effectsreed switch closure in the implanted device to initiate a telemetrysession. Thereafter, uplink and downlink communication takes placebetween the implanted device's transmitter and receiver and a receiverand transmitter disposed within the programming head.

As previously noted, primary control circuit 220 includes centralprocessing unit 232 which may be an off-the-shelf programmablemicroprocessor or microcontroller, but in an embodiment of the inventionit may be a custom integrated circuit. Although specific connectionsbetween CPU 232 and other components of primary control circuit 220 arenot shown in FIG. 2, it will be apparent to those of ordinary skill inthe art that CPU 232 functions to control the timed operation of senseamplifier circuit 224 under control of programming stored in RAM/ROMunit 230. In addition to or as an alternative embodiment digital logic238 may also be provided and utilized. In another alternativeembodiment, a processing module that contains either a processor ordigital circuitry may also be utilized. Those of ordinary skill in theart will be familiar with such an operative arrangement.

With continued reference to FIG. 2, crystal oscillator circuit 228provides main timing clock signals to primary control circuit 220. Thevarious components of implantable medical device 100 are powered bymeans of a power source such as a battery 239, which is contained withinthe hermetic enclosure of implantable medical device 100. For the sakeof clarity in the figures, the connections between the battery 239 andthe other components of implantable medical device 100 are not shown.Sense amplifier 224 is coupled to monitoring/sensing elements 30 and 32.Where cardiac intrinsic signals are sensed, they may be sensed by senseamplifier 224 as substantially described in U.S. Pat. No. 6,505,067.

Processing by CPU 232 or digital logic 238 allows detection of cardiacand neural electrical characteristics and anomalies. CPU 232 or digitallogic 238, under control of firmware resident in RAM/ROM 230, mayinitiate recording of the appropriate diagnostic information into RAM ofRAM/ROM 230.

It will be appreciated that alternative embodiments of implantablemedical device 100 may also be utilized. As discussed above, implantablemedical device 100 may sense any number of physiologic conditions of thepatient 12 for purposes of detecting, and storing data relating to, anynumber of the neurological events. For example, various lead(s) may beused to facilitate detection of a neurological event and the recordingof data and signals pre and post event.

In another aspect of the invention, an electrode 32 located distally ona sensor stub may be used to facilitate detection of a neurologicalevent and the recording of data and signals pre and post event. See U.S.Pat. No. 5,987,352. In alternative embodiments of the invention, theimplantable medical device 100 may also sense respiration parameterssuch as respiration rate, minute ventilation and apnea via measuring andanalyzing the impedance variations measured from the implantedimplantable medical device 100 case to the electrode located distally onthe sensor stub lead as substantially described in U.S. Pat. Nos.4,567,892 and 4,596,251.

In yet another aspect of the invention, an external wearable device suchas a wearable patch, a wristwatch, or a wearable computing device may beused to continuously sense implantable medical device cardiac functionsof patient 12. Optionally, a button (not shown) on the external wearabledevice may be activated by the patient 12 (or a caregiver) to manuallyactivate data recording (for example, in the event the patient isexperiencing a neurological event). The external wearable device maycomprise an amplifier, memory, microprocessor, receiver, transmitter andother electronic components as substantially described in U.S. Pat. No.6,200,265. In the embodiment of a wearable patch, the device may consistof a resilient substrate affixed to the patient's skin with the use ofan adhesive. The substrate flexes in a complimentary manner in responseto a patient's body movements providing patient comfort and wearability.The low profile patch is preferably similar in size and shape to astandard bandage, and may be attached to the patient's skin in aninconspicuous location.

The above embodiments illustrate that the disclosed techniques may beimplemented within any number of medical device systems (drug delivery,electrical stimulation, pacemaking, defibrillating, cochlear implant,and/or diagnostic). Thus, for example without limitation, the implantedmedical component may utilize one or more monitoring elements (e.g.,electrodes or other sensors), a memory component having a plurality ofdata structures (and/or data structure types), a processing component(such as a CPU or digital logic), and a telemetry component.

FIG. 4 shows apparatus 1200 that supports reporting physiological datain accordance with an aspect of the invention. With apparatus 1200, theimplanted component 1205 of the medical device system communicates withthe relaying module 1215 via telemetry antenna 1210. Similarly, theexternal component 1225 communicates with the relaying module 1215 viaantenna 1220. In the embodiment, a telemetry link 1221 between relayingmodule 1215 and antenna 1220 comprises a 3 MHz body wave telemetry link.To avoid interference, the relaying module 1215 may communicate with theexternal and implanted components using differing communication schemes.In some embodiments, the reverse direction and the forward direction oftelemetry link 1221 may be associated with different frequency spectra.The relaying module 1215 thereby provides a greater range ofcommunications between components of medical device system. For example,in the embodiment of an implanted system, an external programmer maycommunicate with an implanted device from a more remote location. Theexternal programmer may be across the room and still be in communicationvia the relaying module 1215. With the telemetry booster stage, the useof an implanted system is more convenient to the patient, in particularat night while sleeping or when taking a shower, eliminating the needfor an external device to be worn on the body.

As shown in FIG. 5, in an embodiment, the system allows the residential,hospital or ambulatory monitoring of at-risk patients and theirimplanted medical devices at any time and anywhere in the world. Medicalsupport staff 1306 at a remote medical support center 1314 mayinterrogate and read telemetry from the implanted medical device andreprogram its operation while the patient 12 is at very remote or evenunknown locations anywhere in the world. Two-way voice communications1310 via satellite 1304, via cellular link 1332 or land lines 1356 withthe patient 12 and data/programming communications with the implantedmedical device 1358 via a belt worn transponder 1360 may be initiated bythe patient 12 or the medical support staff 1306. The location of thepatient 12 and the implanted medical device 1358 may be determined viaGPS 1302 and link 1308 and communicated to the medical support networkin an emergency. Emergency response teams can be dispatched to thedetermined patient location with the necessary information to preparefor treatment and provide support after arrival on the scene. See, e.g.,U.S. Pat. No. 5,752,976.

An alternative or addition to the system as described above inconjunction with FIG. 5 is shown in the system 1450 of FIG. 6, whichshows a patient 12 sleeping with an implantable Monitor 1458 and/oroptional therapy device as described above in connection with theabove-described systems. The implantable device 1458, upon detection ofa neurological event may alert a remote monitoring location via localremote box 1452 (as described in U.S. Pat. No. 5,752,976), telephone1454 and phone lines 1456 or the patient's care provider via an RF link1432 to a pager-sized remote monitor 1460 placed in other locations inthe house or carried (i.e., belt worn) by the care provider 1462. Theremote caregiver monitor 1460 may include audible buzzes/tones/beeps,vocal, light and/or vibration to alert the caregiver 1462 of patient'smonitor in an alarm/alert condition. The RF link may include RF portablephone frequencies, power line RF links, HomeRF, Bluetooth, ZigBee, WIFI,MICS band (medical implant communications service), or any otherinterconnect methods as appropriate.

Probabalistic Treatment Therapy

Suppose that a subject with seizures is being treated with an open loopcontrol program. This subject may be simultaneously monitored using somemeans to log seizures. Example means include but are not limited to:

-   -   a. Quantifying the signal's seizure content using a method such        as the algorithm in U.S. Pat. No. 5,995,868, without necessarily        using the output to effect changes in real-time;    -   b. Logging time of seizure occurrences as well as brain state        (e.g., awake); physical state (e.g., inactive); cognitive status        (e.g., inattentive); metabolic status (e.g., blood glucose        concentration); brain and body temperature; time from previous        seizure(s); previous seizure(s)' intensity, severity and spread;        and exposure to precipitants (e.g., light as measured using a        light meter), without necessarily using the data to effect        changes in real-time. Other markers of cerebral excitability        such as GABA and glutamate concentrations and others listed in        U.S. Pat. No. 6,934,580 may be included in the estimation of        seizure probability; and/or    -   c. an event button with clock and memory.

Let t=time elapsed since beginning of delivery of a particular therapyprogram. Let {t_(i)|i=1, 2, . . . } be a sequence of reference timepoints (“fiducial times”). Let t_(REL)=t (mod max {t_(i)|t_(i)<=t}).Here t_(REL) corresponds to the time elapsed since the most recentfiducial time. Examples:

-   -   a. t_(i)=sequence of times corresponding to midnight on each day        of monitoring. Then t_(REL) is simply the time of day.    -   b. t_(i)=sequence of times corresponding to beginning of menses        in a female subject. Then t_(REL) is the time in the subject's        menstrual cycle.    -   c. t_(i)=sequence of times corresponding to beginning of each        administration of treatment or intervention. Then t_(REL) is the        time elapsed since the beginning of the last stimulation.    -   d. t_(i)=sequence of seizure start (or end) times. Then t_(REL)        is the time elapsed since the start (resp., end) of the last        seizure.

At any point in time, the probability of a seizure occurring is given byP(t)=P(Sz occurring at time t). Knowing P(t) would be of value intreating epilepsy. The inventors have developed a framework that doesnot rely on conventional on-line, real-time seizure detection orprediction but utilizes available information (history) to issuewarnings and/or deliver therapy based on this developed probabilityfunction (as opposed to specific, binary, event detections). Thisprobability function and related decisions of whether or not to issue awarning or deliver therapy can incorporate useful dependency of factorssuch as type of present activity and its inherent risk of injury, socialembarrassment, and importance to preserve cognitive functions.

For any relative time, τ in Range {t_(REL)}, given a reasonable lengthof monitoring, T, of the subject utilizing the current control program,one may compute and use the empirical probability of a seizure occurringat any point in time for this subject as:pE(τ; T)=(# of seizures with t _(REL)=τ)/(# of times t _(REL)=τ).

This “empirical probability density of seizures relative to time withrespect to a fiducial sequence” is an approximation of the unknownprobability of interest, namely, P(Sz occurring at time t_(REL)=τ)

This empirical probability function can be used to compare one therapycontrol program against another (or against the untreated subject) inorder to determine which is more effective and enables adjustment oftherapy to improve efficacy.

ILLUSTRATIVE EXAMPLES

As depicted in FIG. 7, the probability of seizure occurrence is known tochange as a function of time of day (from Osorio I, Frei M G, Manly B FJ, Sunderam S, Bhavaraju N C, and Wilkinson S B. J Clin Neurophysiol.2001 November; 18(6):533-44). Moreover, it is known that some patientsare much more likely to have seizures while they are asleep (“nocturnalepilepsy”). By examining seizure frequency of occurrence as a functionof time of day, one can determine the effect of circadian variations onseizures for a particular subject and use this information to bettercontrol their seizures as illustrated in the following example.

Example 1

Suppose a subject with primarily nocturnal seizures is monitoredcontinuously for one month (or some period of time that yields arepresentative or useful sample) with no therapy enabled, and then for asecond month (or other period), while being treated with an open loopcontrol program that consists of 5 mA of stimulation at 100 Hz for 1minute every 10 minutes (i.e., on 1 minute, off 9 minutes). Usingtime-of-day in generating t_(REL) (as in above example), the graphs inFIG. 8 illustrate PE(τ) for months 1 (solid) and 2 (dash-dot),respectively. In this example, it is apparent that the therapy programhad a seizure-reduction effect during the night, but may have increasedseizure frequency during the day. Given this information, the user(subject or caretaker) may improve the overall efficacy of therapy bydeveloping a new control program that is obtained by combining theapproaches to produce a second control program that is equal to theprevious one (on 1 minute, off 9 minutes) during the night, but is offcompletely between 8:30 and 15:30. Under the assumption that the effectof therapy is relatively instantaneous and lacking significant temporalcarry-over effect, this revised control can be expected to result inimproved therapy for the subject. While one skilled in the art willappreciate that the aforementioned assumptions need not be valid, theinformation obtained from the method allows the user to quantify thelinearity of the response and the size and duration of the carry-overeffect and to suitably modify the control program.

FIG. 9 depicts observed changes in seizure duration and intensity as afunction of time from onset of stimulation (from S. Sunderam et al.,Brain Research 918 (2001) 60-66). In another embodiment, the times ofstimulation are used as fiducial times to examine the effect on seizurelongevity and optimize the stimulation parameters. Seizure probabilityand severity may also be estimated as a function of time of delivery oftherapy (such as electrical stimulation) and may depend upon otherrelevant parameters such as intensity, duration, frequency, stimulationpolarity, etc.

Example 2

Consider a subject that is being treated with a closed-loop stimulationprogram. For example, after a period of no therapy, the treatmentprogram provides for 2.5 s of continuous stimulation to the anteriorthalamic nucleus, triggered by every other seizure detection (generatedby an automated seizure detection algorithm). The subject continues tohave seizures, so the stimulation duration is increased to 30 s ofcontinuous stimulation, administered to the same brain location, againtriggered by every other seizure detection. After a period of time, themonitoring data is collected and analyzed as described above with thefiducial times equal to the starting time of each stimulation. Thecorresponding probabilities of seizure survival, relative to elapsedtime from start of stimulation, are shown in FIGS. 10 and 11. In thismanner, the system enables the user to determine the duration ofstimulation that has optimal effect in terms of seizure reduction(approximately 15 s), beyond which efficacy is not improved further.

FIG. 10, depicts a subject where every other seizure is treated by 2.5 sstimulation beginning at seizure onset. The curves show probability ofbeing in seizure as a function of time from beginning of seizure. Theupper curve indicates probability for stimulated seizures, and the lowercurve represents those seizures that were not stimulated. No significantdifference is evident.

In FIG. 11, depicts a subject where every other seizure is treated by 30s stimulation beginning at seizure onset. The curves show probability ofbeing in seizure as a function of time from beginning of seizure. Thelowest curve indicates probability for stimulated seizures, the middlecurve indicates probability for those seizures that were not stimulated,and the highest curve indicates the baseline probability frompre-treatment phase recordings.

Example 3

A subject that is being treated with an open-loop therapy may beequipped with a device for intensive continuous monitoring of biologicalsignals (such as EEG or EKG), which will detect and quantify features ofthese signals (e.g., epileptiform brain activity or heart rate changes)associated with seizures for a period of time (e.g., 48 hr). Themonitored activity will be analyzed with respect to some fiducial timesequence (e.g., times of onset of stimulation delivery, times ofchanging of stimulation intensity, time of day, etc.) and the empiricalprobability density of seizures relative to time with respect to thefiducial sequence is generated.

FIG. 12 provides an illustration of such information, in which thefiducial times are the times of onset of trains of electricalstimulation delivered for 30 s every 10 minutes. From this analysis itbecomes apparent that the open-loop stimulation program provides verylittle immediate effect, but has a carry-over, protective effect againstseizures that lasts for 2.5 minutes beyond the end of stimulation. Thisimplies that the open-loop stimulation program should be altered toprovide 30 s of stimulation every 3 minutes. Similar subsequent analysiscan be used to determine the potential benefit of additional fine-tuningof the therapy program.

The approach illustrated in the above example can be indirectly testedin future open-loop trials, by measuring changes in seizure frequencyover pre-specified time periods as a function of stimulation cyclelength (e.g., 1 min ON-5 min OFF vs. 1 min ON-2.5 min OFF); greaterreductions in seizure frequency with shorter off cycles than with longeroff cycles would demonstrate the direction and benefit of utilizing“carry-over” effect information in seizure prophylaxis or abatement.Applicants note that potentially greater benefits may be provided withstimulation applied at relatively high frequencies. For example,Applicants have determined that applying stimulation pulses atfrequencies such as 175 Hz to the anterior thalamic nuclei (orneighboring locations) may allow for substantial reductions in seizuresin patients that suffer from otherwise inoperable pharmaco-resistantseizures if the stimulation pulses are provided at a rate of one minutestimulation-on, five minutes stimulation-off. High frequency electricalstimulation, defined as 100 Hz minimum, may (1) induce synapticplasticity in the form of short-term depression, long-term depression,or both; (2) upregulate glutamic acid decarboxylase and downregulatecalcium-and calmodulin-dependent protein kinase II, the net effect ofwhich is to enhance inhibition at or near the stimulated site. Inaddition, high frequency electrical stimulation increases the seizurethreshold in the rat pentylenetetrazol model when delivered to theanterior thalamic nuclei and therefore may have a similar effect inhumans. Such a stimulation signal may be applied with an intensity of 5volts and an initial round of closed-loop testing may be used todetermine the stimulation signal's parameters such as shape, duration,amplitude and any other signal parameter that may be controlled.

The intervention delivered by the probabilistic closed-loop methodsdisclosed herein may be tailored for individual or subject-specificwarning and/or treatment based on the frequency and/or severity ofseizures, circadian patterns, occupational hazards, social factors,employment demands, etc.

The probabilistic closed-loop approach, which encompasses the concept of“intelligent open-loop,” may be used to issue “graded” or incrementalwarnings and/or therapy. For example, the seizure probability in a givenpatient is estimated to be 40% at a given time. This probabilityestimate may trigger a warning (vibration or sound) that is half asintense as one associated with a probability twice as high (i.e., 80%).The intensity or type of warning in this embodiment changes as afunction of changes in probability, either decreasing or increasing as afunction of its value. Further, a warning associated with a certainprobability estimate may change as a function of risk of injury or ofsocial embarrassment should a seizure occur; a 40% seizure probabilityin a patient sitting in a chair at home would be much less intense thanif the subject was operating a vehicle. Temperature sensors,accelerometers and/or EKG among other means, may be used to determinethe level of activity (sedentary vs. in motion) and its relativeduration to automatically adjust the level or type of warning. Operationof power equipment or of vehicles may be factored into the warning scaleby the patient simply pressing a button prior to initiating theseactivities. Cars or power equipment may be also equipped with devicesthat upgrade the warning level as they are turned ON and a disablingdevice that communicates with the patient's device may be activatedshould the seizure probability be at an unsafe level. An identicalapproach may be taken for therapy: The type of therapy andparameters/dose used when the seizure probability is 40% may bedifferent that when it is 80% or when the subject changes activity froma low to a high risk for injury.

In other embodiments, other thalamic stimulation targets may be appliedfor treatment of the neurological disorder, including particularlymesial temporal and mesial frontal intractable epilepsies. These targetsinclude anterior thalamic nuclei, nucleus Reticulatus polaris, nucleusLatero-polaris, nucleus Antero-medialis, nucleus Ventro-oralis Internus,nucleus Antero-principalis and nucleus Lateropolaris. It is noted thatwhile the anterior thalamic nuclei is a known target for stimulation,success has been experienced when stimulating neighborhood targets.Thus, in an embodiment a stimulation target may be a region, which isdefined as more than one nucleus or thalamic structure, rather than asingle thalamic nucleus or structure. In addition, another possibletarget is the Campus Forelli Pars H2, which is not a direct neighbor ofthe anterior thalamic nuclei. Other targets are also contemplated andwould vary depending on the type of disorder.

While it has been determined that neighborhood targets may also providesuitable candidates so as to allow the physician implanting theelectrode in the target greater latitude in the selection of the target,for certain treatment procedures it is desirable to stimulate the sametarget in both the right and left hemisphere of the patient's brain.Therefore, the evoked response methodology discussed below providescertain benefits when attempting to implant electrodes in particularregions and/or locations of the brain.

In general, evoked responses are generated by applying a stimulationpulse with an implanted target electrode and measuring the resultantresponse at other electrodes such as scalp electrodes or other depthelectrodes. Measurements of amplitude, latency and conduction velocityprovide information that allows a determination of the location of theimplanted electrode being used to stimulate. Additionally, themorphology and polarity of the responses provide information about theuniformity of electrode placement intra- and inter-individually sincethey depend on the nature, location and orientation of the currentsources, as well as on volume conduction characteristics which aredetermined by the electrical and geometric properties of the tissue.This location information also provides information on the connectionthat the electrode stimulation site has to the desired treatment site,thus indicating whether the stimulation site is a neighboring site ofthe desired treatment site. In an embodiment, evoked responses may beused to assess the precision of lead placement intra- andinter-individually. This complements MRI or other imaging basedtechniques and is particularly useful for targets that as the ATN, thanunlike the STN (for treatment of movement disorders) appear to lackeasily identifiable electrophysiological markers. Accurate in-vivolocalization of electrodes/contacts and identification of functional orelectrographic target markers loom as challenges that must besuccessfully addressed to identify, with reproducible accuracy inhumans, structures with seizure gating capabilities and properly assessthe therapeutic value/ratio of open- or closed-loop electricalstimulation. Although evoked responses techniques as used in a recentinvestigation do not provide direct information about lead localization,they may be used (a) to indirectly determine if the EpileptogenicZone(s) and the leads'targets share anatomical connections; and (b) astools to assess intra- as well as inter-individual uniformity/precisionof lead placement. Applicants have determined that the intra- andinter-individual differences in evoked responses in these subjects mayaccurately predict the probable differences in lead location. The basisfor this claim is that the potential or waveform (defined by polarity,morphology and amplitude) at any location in the brain may varydepending on: (1) the nature, location and orientation of the currentsources; and (2) volume conduction characteristics which are determinedby the electrical and geometric properties of the tissue. That is,potentials or waveforms of different amplitude, morphology and polarity,recorded from the same site, are not generated by the same currentsource or structure. Indirect or direct electrical stimulation of brainstructures generates reproducible waves or oscillations (i.e., evokedresponses), that may be recorded from the scalp (or intra-cerebrally)and have shapes and latencies that are unique for each structure. Forexample, the responses generated by stimulation of structures involvedin the processing of sensory signals, have characteristic shapes andlatencies that are highly similar among different subjects and areeasily distinguishable, from those generated by structures involved inprocessing acoustic stimuli which are also highly similarinter-individually. It follows, therefore, that direct or indirectstimulation of the same structure in each cerebral hemisphere elicitshighly similar, if not identical, reproducible responses that may berecorded from the scalp, using electrodes placed according to the 10-20system, or, any other standardized system of electrode placement. Forexample, bi-phasic square pulses (0.7 Hz; 0.1 ms/phase; 5.1 mA/phase)may be applied to electrodes near the planned treatment area and theresponses record so as to determine the location of the electrodes.These responses may be also reliably and reproducibly recordedintra-cerebrally from structures connected to those being stimulated.Differences in evoked responses elicited from relatively selectiveunilateral electrical or chemical stimulation of a given cerebralstructure, compared to a) responses elicited by stimulation of thehomologous contra-lateral structure or b) responses elicited in otherindividuals, suggest the structures being stimulated are different.Thus, it can be determined that the leads through which the currents arebeing passed are not in homologous structures or regions. This allowssafe, repetitive and accurate assessment of precision of placementwithout the need to resort to magnetic resonance or computerizedtomography. In addition, precise determination of the placement of theleads can also reduce the subjectivity inherent to visual localizationof leads since evoked responses are quantitative.

It should be noted that evoked responses may be used to find out if thestructure where the stimulation electrode is being placed has functionalconnectivity with the remote area whose abnormal activity is beingcontrolled or abated. The presence of reproducible evoked responses inthe abnormal or treatment area, defined as responses with identicallatency, morphology and amplitude obtained from at least 2 separatestimulation trials, is strong evidence that the stimulation area and theabnormal area have functional connectivity. Furthermore, placement ofthe stimulation electrode may be optimized by monitoring changes inlatency, amplitude and morphology in response to small changes in theposition (in the x, y or z planes) of the electrode or by changing thepart or contact of that electrode through which currents are passed. Ifstimulation parameters are kept constant and a change in the position ofthe contact and/or a change in the contact provides a decreases inlatencies and/or increases in amplitude without changes in overallmorphology then the change indicates improved placement. Evokedresponses may be also used to find out if a stimulation target hasfunctional connectivity with structures in the opposite hemisphere. Thishas important practical and clinical applications: If a structure in onehemisphere has functional connectivity with ipsi-lateral andcontra-lateral homologous structures, stimulation of one side maysuffice, or intermittent stimulation of the two sides may be alternatedto provide full time protection. In other words, the total stimulationenergy may be reduced because only side is stimulated at a time. Thiscan extend the life of an implantable medical device with a limitedpower source and can also potentially reduce any negative cognitiveeffects that the stimulation might have.

FIG. 13 illustrates an embodiment of implanting and locating electrodesusing evoked responses. In step 410 an electrode is positioned in afirst hemisphere of the patient's brain. In an embodiment, the electrodemay be shaped to stimulate more than one target site (for example, maybe shaped like a shaft) and in another embodiment the electrode may beone of a plurality of electrodes in an array on a lead.

In step 420, a stimulation pulse is applied and the evoked responsemeasured. In step 320, the evoked response is compared to an evokedresponse of an electrode positioned in a desired location, either in thecurrent patient or in another patient. If the electrode is not in thedesired position, steps 410 and 420 are repeated. It should be notedthat in an embodiment where the electrode is one of a plurality ofelectrodes in an array, some portion of the electrodes may be selectedand stimulated and step 420 may be repeated for each contact that isselected. As can be appreciated, in such an embodiment there may be noneed to adjust the position of the lead if the first electrode is notproperly positioned, rather the position of the selected contact on thelead can be changed until an electrode is determined to be positioned ina desired location. It should be noted that in a situation where aregion is the intended target, the location of the first electrode isacceptable as long as the location is within the target region.

Once the first electrode is properly positioned, a second electrode ispositioned in a second hemisphere in step 440. For example, if the firstelectrode is positioned in the left hemisphere, then the secondelectrode may be positioned in the right hemisphere. In step 450 the astimulation pulse is applied to the second electrode and in step 460 acheck is made to see if the location of the second electrode correspondto the position of the first electrode. If the location of the secondelectrode is determined to not match the desired location, steps 440-460may be repeated. Therefore, in an embodiment the position of the secondelectrode can be made to correspond to the position of the firstelectrode by ensuring the evoked response of the second electrode issubstantially identical to the evoked response of the first electrode.

It should be noted that modifications and additions to the steps of theprocess depicted in FIG. 13 are contemplated. For example, if the secondelectrode is one of a portion of electrodes in an array, the positioningof the second electrode can be simply selecting a different electrodefrom the array of electrodes. In addition, if the evoked response isdetermined to match an evoked response associated with a particularlocation, an indication, which may be textual or graphical, can beprovided on a display so that the person implanting the electrode has avisual feedback on the location of the electrode. Therefore, thedepicted process is representative and is not intended to be limitingunless otherwise noted.

FIG. 14 illustrates an embodiment of applying open-loop stimulation inaccordance with one or more embodiments of the present invention. Firstin step 510, a plurality of electrodes is implanted at the desiredlocation. It should be noted that precise electrode placement is not aneasy task; therefore, a check may be made to determine the location of aplurality of implanted electrodes during the implanting process asdiscussed above in FIG. 13. It should be noted that plurality ofelectrodes may be situated in an array and may be situated on more thanone lead. In step 520, an initial analysis is conducted with theelectrodes. This analysis may use the probabilistic algorithms discussedabove to determine stimulation parameters for reducing the occurrence ofseizures when stimulation is applied at the one or more electrodes. Itshould be noted that using multiple electrodes has the advantage ofpotentially being able to stimulate a greater volume of brain tissueand, therefore, the application of a stimulation pulse to two or moreelectrodes may be desirable for certain types of treatment.

Once the parameters are determined, an implantable medical device may beimplanted in step 530. It should be noted that for situations whereopen-loop stimulation is being used, the implanted medical device doesnot need to sense neurological signals and does not have to store eventsin an on-board memory. However, if desired, the stimulation device mayalso include recording features so that sensed signals may be analyzedat a later time. In addition, the implantable medical device may also beconfigured to record events, such as seizures, generated by a useractuating a programmer. In such a configuration the implantable medicaldevice may communicate via telemetry in a known manner.

In step 550, the implantable medical device begins to providestimulation in an open-loop fashion. In an embodiment, the stimulationmay be bi-phasic at a high frequency such as 175 Hz and the electrodesthat are selected may be the cathode (−) and the device case, which maybe in the patient's chest, the anode (+) (a “monopolar” typeconfiguration). Such a configured allows the electrodes that are in theproper location to encompass as much of the stimulation target aspossible. In an embodiment the stimulation may be at an intensity of 5volts with a repeating pattern of a period of one minute of stimulationfollowed by five minutes of no stimulation. It has been determined that,while other patterns are possible, such a pattern is well tolerated ininitial patient studies and has a substantially beneficial effect on thereduction of seizures while having minimal or at least an acceptableimpact on cognitive and motor-sensory functionality so as to improve thepatient's quality of life.

In step 560, analysis is conducted to determine the efficacy of thetreatment program. In an embodiment where the implanted medical devicedetects and stores events such as seizures, the information may bedownloaded from the implanted device in a known manner and analyzed. Ascan be appreciated, with a suitable relay system this process can beinitiated and conducted remotely. The analysis may include adetermination of the reduction in seizure frequency and/or severity aswell as an evaluation of cognitive and motor-sensory skills to determinea more complete picture of the effects of the treatment.

As can be appreciated, additional steps may be added and steps may beomitted or reordered as desired. For example, the implantable medicaldevice may be implanted and first used in a closed-loop configuration todetermine the desired stimulation parameters and/or the location of theelectrodes and then be switched to an open-loop stimulation mode toconserve power.

The usefulness of the invention should be apparent to one skilled in theart. The use of any and all examples or exemplary language herein (e.g.,“such as”) is intended merely to better illuminate the invention anddoes not pose a limitation on the scope of the invention unlessotherwise claimed. No language in the specification should be construedas indicating any non-claimed element as essential to the practice ofthe invention.

The present invention has sometimes been described in terms of preferredand illustrative embodiments thereof. Numerous other embodiments,modifications and variations within the scope and spirit of the appendedclaims will occur to persons of ordinary skill in the art from a reviewof this disclosure.

1. A method of treating a patient with a neurological disorder,comprising: (a) implanting a first electrode approximate a first targetsite in a first hemisphere of the patient's brain; (b) determining anevoked response of the first electrode; (c) implanting a secondelectrode in a location approximate a second target site in a secondhemisphere of the patient's brain; and (d) verifying the location of thesecond electrode corresponds to the location of the first electrode byusing an evoked response of the second electrode.
 2. The method of claim1, wherein the verify in (d) comprises (i) determining the evokedresponse of the second electrode; and (ii) in response to the evokedresponse of the second electrode not corresponding to the evokedresponse of the first electrode, adjusting the position of the secondelectrode until the evoked response of the second electrode doescorrespond to the evoked response of the first electrode.
 3. The methodof claim 1, further comprising: (e) adjusting a position of the firstelectrode in response to the evoked response.
 4. The method of claim 1,wherein the first target site is a region.
 5. The method of claim 1,wherein the evoked response comprises parameters associated withamplitude, latency, conduction velocity, number of peaks, polarity andshape.
 6. The method of claim 1, wherein the first target site iscomprises a location selected from a list consisting of anteriorthalamic nuclei, nucleus Reticulatus polaris, nucleus Latero-polaris,nucleus Antero-medialis, nucleus Ventro-oralis Internus, nucleusAntero-principalis, nucleus Lateropolaris and Campus Forelli Pars H2. 7.The method of claim 1, further comprising: (e) verifying a location ofthe first electrode corresponds a desired location associated with atreatment area.
 8. The method of claim 7, wherein the verifying in (e)comprises: (i) obtaining a reproducible evoked response with welldefined latency, amplitudes and morphology in at least two separatestimulation trials; (ii) comparing the evoked response to an expectedevoked response; and (iii) in response to a determination that theevoked response does not correspond to the expected evoked response,adjusting the position of the first electrode until the evoked responseof the first electrode does correspond to the expected evoked response.9. The method of claim 1, further comprising: (e) implanting animplantable medical device in the patient; and (f) applying aclosed-loop stimulation pattern to the first and second electrodes. 10.The method of claim 9, wherein the applying open-loop stimulationpattern in (f) comprises: (i) configuring the first and second electrodeas a cathode; and (ii) configuring a case of the implantable medicaldevice as an anode.
 11. The method of claim 10, wherein the applying ofopen-loop stimulation in (f) comprises: (iii) providing stimulation atbetween 145 Hz and 200 Hz in a repeating pattern that includes oneminute of stimulation followed by five minutes of no stimulation. 12.The method of claim 11, wherein the stimulation is applied at 175 Hz atan intensity of 5 volts.
 13. A method of treating a patient with aneurological disorder, comprising: (a) implanting a plurality ofelectrodes approximate a target region of the patient's brain; (b)verifying the location of at least one of the plurality of electrodesusing an evoked response; (c) determining stimulation parameters usingthe implanted electrodes and a closed-loop detection algorithm; (d)coupling the plurality of electrodes to an implantable medical device;and (e) applying open-loop stimulation to the plurality of electrodeswith the implanted medical device based on the determined stimulationparameters.
 14. The method of claim 13, wherein the verifying of thelocation in (b) comprises comparing the morphology, latency and polarityof the evoked response to determine the location of the implantedelectrode.
 15. The method of claim 13, wherein the applying of open-loopstimulation comprises: (i) configuring the plurality of electrodes as acathode; and (ii) configuring a case of the implantable medical deviceas an anode.
 16. The method of claim 13, wherein the evoked response isdone while implanting the plurality of electrodes.
 17. The method ofclaim 16, wherein the evoked response is measured using scalpelectrodes.
 18. The method of claim 16, wherein the evoked response ismeasured using intracranial electrodes.
 19. The method of claim 13,wherein the verifying the location of the at least one electrodeincludes a determination of functionality connectivity between astructure being stimulated by the electrode and one of an ipsilateraland a contralateral structure, and wherein the applying of the open-loopstimulation stimulates a single side.
 20. The method of claim 13,wherein the verifying the location of the at least one electrodeincludes a determination of functionality connectivity between astructure being stimulated by the electrode and one of an ipsilateraland a contralateral structure, and wherein the applying of the open-loopstimulation alternates stimulation between sides.
 21. A computerreadable medium comprising computer readable instructions, comprising:(a) receiving an evoked response generated by applying a stimulationpulse applied to an implanted electrode; (b) determining that the evokedresponse matches an known evoked response; and (c) providing anindication that the evoked response matches the known evoked response.22. The computer readable medium of claim 21, wherein the indication isrendered on a display.
 23. The method of claim 22, wherein theindication provides information regarding a location of the implantedelectrode.
 24. A method of determining the existence of functionalconnectivity between a stimulation target and a treatment area,comprising: (a) implanting a first electrode in the stimulation target;(b) implanting a second electrode in the treatment area; (c) stimulatingthe first electrode with an electrical pulse; (d) obtaining an evokedresponse from the second electrode; and (e) if the evoked response isnot reproducible, repositioning the first electrode and repeating(c)-(d) until a reproducible evoked response is obtained from the secondelectrode.
 25. The method of claim 24, wherein the treatment areacomprises an abnormal brain area.